Certain oxy-substituted benzo quinolizinium compounds and their use

ABSTRACT

(1) BENZO(B)QUINOLIZINIUM COMPOUNDS DISUBSTITUTED IN THE 8,9- AND 9,10-POSITIONS AND TRISUBSTITUTED IN THE 8,9,10-POSITIONS WITH HYDROXY, LOWER ALKANOXY AND LOWER ALKANOYLOXY GROUPS, AND (2) LOWER ALKYL AND 11-AMINO SUBSTITUTED DERIVATIVES, THEREOF ARE USEFUL AS CARDIOVASCULAR AGENTS, AS AGENTS AFFECTING THE CENTRAL NERVOUS SYSTEM, AND AS ANTIPYRETIC AGENTS.

United States Patent Oflice 3,712,946 Patented Jan. 23, 1973 US. Cl.424-258 3 Claims ABSTRACT OF THE DISCLOSURE (l) Benzo[b]quinoliziniumcompounds disubstituted in the 8,9- and 9,10-positions andtrisubstituted in the 8,9,10-positions with hydroxy, lower alkanoxy andlower alkanoyloxy groups, and (2) lower alkyl and ll-arnino substitutedderivatives thereof are useful as cardiovascular agents, as agentsaffecting the central nervous system, and as antipyretic agents.

This application is a divisional of Ser. No. 857,658, filed Sept. 11,1969, now US. 3,565,899 which is a continuation-in-part of Ser. No.603,418 filed Dec. 21, 1968, now abandoned.

This invention relates to certain hydroxy-, alkanoxyandalkanoyloxy-substituted benzo[b]quinolizinium compounds and derivativesthereof, to processes for their preparation, and to their uses. Moreparticularly, this invention relates to 8,9- and 9,l-dihydroxy-,dialkanoxyand dialkanoyloxybenzo[b]quinolizinium compounds, to 8,9,10-trihydroxy-, trialkanoxyand trialkanoyloxybenzo[b]- quinoliziniumcompounds and to certain of their alkyl and amino substitutedderivatives.

The compounds of this invention can be represented by the followinggeneral formula:

in which R is hydrogen or lower alkyl,

The term lower alkyl as used herein alone or in lower alkanoxy and loweralkanoyloxy means saturated monovalent aliphatic radicals of the generalformula C H wherein m represents an integer of 6 or less, and isinclusive of straightand branched-chain groups such as methyl, ethyl,n-propyl, isopropyl, n-butyl, etc.

The compounds of this invention are pharmaceutically active agents. Theyare useful as cardiovascular agents, particularly for lowering bloodpressure, as agents affecting the central nervous system, particularlyas tranquilizers, and as antipyretic agents.

These compounds can be conveniently made from starting materials havingthe following structure:

in which R and X have the meaning ascribed to them in Formula I,

at least one of Y and Y is lower alkanoxy or lower alkanoyloxy and theother of Y or Y is hydrogen, lower alkanoxy or lower alkanoyloxy, and

Y, is lower alkyl or lower alkanoyl.

Compounds of this structure can be made by methods well known in the artfrom the corresponding aldehydes, carboxylic acids, esters, andalcohols, or by the known method of halomethylation of the appropriatebenzene derivative. This starting compound is then quaternized with a2-pyridinealdoxime to yield a solt consisting of a mixture of syn andanti isomers, having the following structure:

1 H=NOH (III) in which R R X, Y Y and Y have the meanings ascribed tothem in Formulae I and II above.

The quaternary salt intermediate is then cyclized with a concentratedhalogen acid to yield principally a benzo [bJquinolizinium halide salthaving the following structure:

I Y2 N I we R1 (IV) and also smaller amounts of the ll-amino derivativeIf hydroxy rather than lower alkanoxy or lower alkanoyloxy compounds aredesired, compounds of Formulae IV and V can be hydrolyzed. To obtain thecorresponding lower alkanoyloxy compound, the hydroxy compound istreated with an appropriate acylating agent. Thus, by this generalmethod, all compounds encompassed by Formula I can be prepared.

As an alternative, a picolinic aldehyde may be used in thequaternization step instead of the 2-pyridine-aldoxime. In this case,the cyclization step yields the benzo[b]quinoliziniurn holideunsubstituted in the ll-position.

To illustrate this process more specifically, the following is a briefdescription of the method of preparation of9,10-dihydroxy-7-methylbenzo[b]quinolizinium bromide, and itsdimethoxy-, 11-hydroxy-, ll-amino-, and diacetoxy analogs. The startingcompound, 2-methyl-4,5-dimethoxybenzyl bromide O OH:

HsO- CHzBr can be conveniently prepared by bromomethylation of 3,4-

dimethoxymethylbenzene using either brornomethyl ether orparaformaldehyde and aqueous hydrobromic acid. On

quaternization with 2-pyridinealdoxime, 1-(4,5-dimthoxy-Z-methyl)-benzyl-2-formylpyridinium bromide oxirne OCH:

N el H3 H=N O H (VII) is formed. This salt is then cyclized withhydrobromic acid to yield a mixture of 9,10-dimethoxy-7-methylbenzoCHaO- I and 9,10 dimethoxy 11-amino-7 -methylbenzo[b]quinoliziniumbromide OCHa NH:

CHaO- B e N e3 CH3 which may be separated by fractional crystallizationfrom ethanol. The compound of Formula VII may then be hydrolyzed toyield 9,l-dihydroxy-7-methylbenzo[b] quinolizinium bromide and thecompound of Formula IX hydrolyzed to 9,10,11- trihydroxy-7-methylbenzo[b] quinolizinium bromide OH OH I H0 w o Substitution in the 1-, 2-, 3-,or 4-positions may be achieved through the use of the appropriatelysubstituted 2-pyridinealdoxime or picolinic aldehyde. Thus, the use of4-methyl-2-pyridinealdoxime in the specific illustration above gives onquaternization and cyclization, the 2- methyl-substituted salt asillustrated below:

OCH;

A further alternate method of producing the benzo[b] quinoliziniumcompounds of this invention, unsubstituted in the ll-position, involvesquaternization of an appropriately lower alkanoyloxy-substituted benzylhalide with pyridine-Z-aldehyde acetals and subsequent cyclizationfollowed by hydrolysis to yield hydroxy compounds it desired. Thus, toobtain 9,lO-dihydroxy-7-methylbenzo[b] quinolizinium bromide, thestarting compound is 2-methyl- 4,5-diacetoxybenzyl bromide.

CHaO- Br CHaCO O l C H; (XIII) This is reacted with2-(1,3-dioxolan-2-yl)pyridine to obtain l- (4,5 -diacetoxy-2-methylbenzyl-2- 1,3-dioxolan-2- yl)-pyridinium bromide OCOCHa (XIV) by amethod described by D. L. Fields, I. B. Miller, and D. D. Reynolds, J.Org. Chem. 29, 2640 (1964). This salt is then cyclized with stronghydrobromic acid to yield 9,1 0-hydroxy-7-methylbenzo [b] quinoliziniumbromide directly (Formula X).

It will, of course, be realized that by proper choice of startingmaterials, other hydroxy-substituted benzo[b] quinolizinium compounds ofthis invention can be prepared.

Other methods may be used to obtain quaternary salt intermediatesanalogous to those illustrated in Formulae III, VII and XIV. Forexample, salts of this type may be obtained by quaternization of theappropriately substituted benzyl halides with certain Z-substitutedpyridine derivatives. More specifically, they may be obtained byquaternization of (1) alkoxybenzyl halides With 2-pyridinealdehydeacetals, (2) alkanoyloxybenzyl halides with Z-pyridinealdehydesemicarbazones and (3) alkanoyloxybenzyl halides with2-pyridinealdoximes. Also useful are the quaternary salts obtained byreaction of alkoxy-substituted benzyl halides with2-pyridinecarboxaldehyde semicarbazones and with substituted andunsubstituted hydra'zone. For example, treatment of 1-(3,4-dimethoxy-2-methyl)benzyl-2-formylpyridinium bromide semicarbazone orphenylhydrazone with 48% hydrobromic acid for extended periods at gave8,9-dihydroxy-7-methylbenzofb] quinolizinium bromide directly.

The present invention comprehends not only the indicated halide salts,but also other pharmaceutically acceptable nontoxic salts of thesecompounds formed by using the appropriate acid such as phosphoric orsulfuric,

acetic, lactic, succinic, malic, phthalic, tartaric, pamoic and thelike.

The compounds of the invention may be used in warmblooded animals,particularly mammals, as medicaments in the form of pharmaceuticalcompositions containing the compounds in admixture or conjunction with apharmaceutical organic or inorganic, solid or liquid carrier for oral,rectal, or parenteral administration. The total daily doses can varyfrom about 0.1 mg./kg. to about 10 mg./ kg. preferably about 0.5 mg./kg.to mg./kg.

The preferred route of administration is the oral route. Suitablecompositions include, without limitation, tablets, capsules, powders,solutions, suspensions, sustained release formulations and the like.

To produce dosage units for peroral application, the compositions ofthis invention may be combined, e.g., with solid pharmaceuticallyacceptable pulverulent carriers such as lactose, saccharose, sorbitol,mannitol; starches such as potato starch, corn starch or amylopectin,also laminaria powder or citrus pulp powder, cellulose derivatives orgelatin, also lubricants such as magnesium or calcium stearate orpolyethylene glycols of suitable molecular weights may be added, to formtablets or press coated tablets. The latter are coated for example, withconcentrated sugar solutions which can contain e.g., gum arabic talcumand/ or titanium dioxide, or they are coated with lacquer dissolved ineasily volatile organic solvents or a mixture of organic solvents.Dyestuffs can be added to these coatings, for example, to distinguishbetween dilferent contents of active substances.

Hard gelatin capsules contain, for example, granulates of the instantcomposition with solid pulverulent carriers such as, e.g., lactose,saccharose, sorbitol, mannitol and further starches such as potatostarch, corn starch or amylopectin, cellulose derivatives or gelatin, aswell as magnesium stearate or stearic acid.

Suppositories containing a compound of the present invention are readilyobtained by techniques well known to those skilled in the art ofcompounding dosage forms. A compound of the present invention isdispersed in a carrier such as cocoa butter and the suppositories formedin the usual way.

The compounds of this invention and the intermediates obtained in theirpreparation are more fully illustrated by the following examples, whichalso show the method of preparing the starting compounds. These examplesare included here for the purpose of illustration and are not intendedas a limitation. All temperatures are in degrees centigrade.

EXAMPLE 1 Preparation of 8,9-dimethoxy-7-methylbenzo[b]quinoliziniumbromide via l-(3,4-dimethoxy-2-methyl)benzyl- 2-formylpyridinium bromideoxime (a) Monobromomethylmethyl ether.-A mixture of methanol (945 g.)and 40% aqueous formaldehyde (500 ml.) was cooled to 10 and saturatedwith hydrogen bromide. The two phases were separated and the lower layerdistilled. After a forerun, 242 g. of the product, B.P. 8688, wascollected.

(b) 3,4-dimethoXy-Z-methylbenzyl bromide (Method A).-A mixture of2,3-dimethoxytoluene (80 g.), monobromomethylmethyl ether (137 g.) andglacial acetic acid (88 ml.) was maintained at 30 for 8 hours. Thereaction mixture was poured into ice-water and the resulting solidfiltered off. Recrystallization from hexane gave 73 g. of the product ascolorless platelets; M.P. 66-68".

Analysis.Calcd for C H BrO (percent): C, 49.00; H, 5.35; Br, 32.39.Found (percent): C, 48.97; H, 5.40; Br, 32.39.

(Method B).A mixture of 2,3-dimethoxytoluene (91 g.), paraformaldehyde(2 0 g.), 48% hydrobromic acid (68.5 ml.), and benzene (300 ml.) wascooled to 0 with stirring and was saturated with hydrogen bromide withice cooling. The organic phase was separated, washed with saturatedbrine, dried over anhydrous magnesium sulfate and the solvent removedunder reduced pressure to give the crude benzylbromide (124 g.). Onerecrystallization from petroleum ether (B.P. 3 060) gave the benzylbromide g.; M.P. 68-70). A further recrystallization raised the M.P. to70-72".

(c) 1 (3,4 dimethoxy 2-methyl)benzyl-Z-formylpyridinum bromideoxime.3,4-dimethoxy-2-methylbenzyl bromide (54 g.) andZ-pyridinealdoxime (27 g.) were dissolved in dimethylformamide (162 ml.)and the solution was maintained at 30 for 18 hours. The crystallineproduct was removed by filtration and the filtrate poured slowly intoethyl acetate (2000 ml.) with stirring. The resulting amorphous solidwas filtered OE and combined with the crystalline material to give atotal yield of 74 g. of the quaternary salt which was used withoutpurification for the next step of the synthesis. Two recrystallizationsfrom methanol gave the pure material as colorless crystals: M.P.166.5-168".

Analysis.--Calcd for c H BrNgO (percent): C, 52.32; H, 5.22; N, 7.63;Br, 21.76. Found (percent): C, 52.32; H, 5.22; N, 7.63; Br, 21.49.

(d) 8,9 dimethoxy 7 methylbenzo[b]quinolizinum bromide. 1 (3,4dimethoxy-Z-methyl)benzyl2-formy1- pyridinium bromide oxime (50 g.) wasdissolved in 48% hydrobromic acid (125 m1.) previously heated to 110 andthe solution was maintained at that temperature for 5 min. The solutionwas poured into tetrahydrofuran (2000 ml.) with stirring and thestirring was maintained for a further 18 hours. Filtration gave 28 g. ofthe product as yellow platelets. Five recrystallizations from ethanolgave 11.5 g. of pure material, M.P. 2225-2245".

Analysis.--Calcd for C -H BrNO (percent): C, 57.49; H, 4.83; N, 4.18;Br, 23.92. Found (percent): C, 57.54; H, 4.82; N, 4.26; Br, 23.83.

EXAMPLE 2 Preparation of 8,9-dimethoxy-7-methylbenzo [b] quinoziniumbromide via 1-(3,4-dimethoxy-2-methyl)benzyl-Z- formylpyridinium bromide(a) 1-(3,4-dim.ethoxy 2 methylbenzyl-2-formylpyridinium bromide-Asolution of 2-pyridinecarboxaldehyde (5.35 g.: freshly redistilled) and3,4-dimethoxy-2- methylbenzyl bromide (12.5 g.: prepared according toMethod A given in Example 1 (b)) in dimethylformamide (30 ml.) wasmaintained at room temperature for 18 hours under an atmosphere ofnitrogen. The reaction mixture was poured slowly with stirring intoethyl acetate (800 ml.) and the resulting yellow precipitate wasfiltered off to give the quaternary salt (13.2 g.: M.P. 11l-112), usedwithout purification for the next step.

(b) 8,9-dimethoxy 7 methylbenzo[bJquinolizinium bromide.-1-(3,4dimethoxy-Z-methylbenzyl)-2-formylpyridinium bromide (2.5 g.) wasdissolved in 48% hydrobromic acid (7.5 ml.) previously heated to 98, andthe solution was maintained at that temperature for 8 minutes. Thereaction mixture was poured into tetrahydrofuran (100 ml.) withstirring. The resulting yellow precipitate was filtered off (1.3 g.:M.P. 211-213") identified as authentic8,9-dimethoxy-7-methylbenzo[bjquinolizinium bromide by IR. spectroscopyand thin layer chromatography (2 developing systems).

EXAMPLE 3 Preparation of 8,9 dimethoxy-7-methylbenzo[b]quinoliziniumbromide via 1-(3,4-dimethoxy-2-methyl)benzyl-2-formylpyridinium bromideethylene acetal (a) 1-(3,4 dimethoxy-Z-methyl)benzyl-Z-formylpyridiniumbromide ethyleneacetal.-A solution of 2-pyridinecarboxyaldehydeethyleneacetal (1.9 g.) and 3,4-dimethoxy-Z-methylbenzylbromide (3.1 g.;prepared according to Method A given in Example 1 (b)) indimethylformamide (10 ml.: freshly dried by passage through a column ofmolecular sieve, activated, Linde type 13X, /a) was maintained at roomtemperature for 18 hours and then poured slowly with stirring into ethylacetate (500 ml.). The resulting precipitate was filtered off to givethe quaternary salt (3.0 g.; M.P. 125-127") used without purificationfor the next step.

(b) 8,9-dimethoxy 7 methylbenzo[bJquinolizinium bromide.1-(3,4-dimethoxy2-methyl)benzyl-Z-formylpyridinium bromide ethyleneacetal (1.1 g.) wasdissolved in 48% hydrobromic acid (2.6 ml.) previously heated to 110,and the solution was maintained at that temperature for 8 minutes. Thereaction mixture was poured into tetrahydrofuran (40 ml.) with stirringand the resulting yellow precipitate was filtered off (0.7 g.; M.P. 218-224.5") and identified as authentic8,9-dimethoxy-7-methylbenzo[b]quinolizinium bromide by LR. spectroscopyand thin layer chromatography (two developing systems).

EXAMPLE 4 11-amino-8,9-dimethoxy-7-methylbenzo [b] quinolizinium bromide1 (3,4-dimethoxy-2-methylbenzyl)-2-formylpyridinium bromide oxime (87.6g.) was dissolved in 48% hydrobromic acid (205 ml.) heated on the steambath. The resulting solution was poured into tetrahydrofuran (4100 ml.)with stirring and the stirring was maintained for a further 18 hours.Filtration gave 64.2 g. of the crude product which was extracted with 2x 4 liter portions of boiling ethanol. The resulting ethanol solutionsdeposited a total of 5.4 g of crystalline material on cooling and thiswas combined with the residue from the ethanol extractions (2.4 g.). Thecombined material was recrystallized twice from ethanol and once fromdimethylsulfoxide to yield 1.2 g. of the pure product, M.P. 263-263.5.

Analysis..-Calcd for C H BrN O (percent): C, 55.02; H, 4.91; N, 8.02;Br, 22.88. Found (percent): C, 54.82; H, 4.88; N, 7.86; Br, 22.90.

EXAMPLE 5 Preparation of 8,9-dihydroxy 7 methylbenzo[b]quinoliziniumbromide via 8,9-dimethoxy-7-methylbenzo[b] quinoliziuium bromide Amixture of 8,9-dimethoxy-7-methylbenzo[bJquinolizinium bromide, preparedaccording to the method of Example 1, and 48% hydrobromic acid ml.) wasrefluxed for 3 hours and the reaction mixture cooled to roomtemperature. The product was filtered oil and recrystallized twice fromdilute hydrobromic acid to give 1.4 g. of the product as yellow needles,M.P. 305-310 dec.

Analysis.Calcd for C H BrNO (percent): C, 54.92; H, 3.95; N, 4.58; Br,26.11. Found (percent): C, 55.03; H, 4.05; N, 4.72; Br, 25.89.

EXAMPLE 6 Preparation of 8,9 dihydroxy 7 methylbenzo[b]quinoliziniumbromide via 1-(3,4-dimethoxy-2-methyl)benzyl-2-formylpyridinium bromidesemicarbazone (a) 1-(3,4 dimethoxy-Z-methyl)benzyl-2-formylpyridiniumbromide semicarbazone.fi8emicarbazide hydrochloride (0.8 g.) wasdissolved in methanol (100 ml.) and potassium carbonate (0.5 g.) wasadded. The solution was filtered and the semicarbazide solution wascooled to room temperature. 1- 3,4-dimethoxy-2-methylbenzyl-2-formylpyridinium bromide (2.0 g.: prepared according to themethod of Example 2 (a)) was dissolved in methanol (50 ml.) and added tothe methanolic semicarbazide. The reaction mixture was stirred at roomtemperature for 18 hours and then poured into ether (1000 ml.). Theresulting precipitate (2.7 g.) was filtered off and recrystallized frommethanol/ethyl acetate to give the quaternary salt (0.2 g.: M.P.178178.5) together with 1.7 g. of less pure material.

(b) 8,9-dihydroxy-7-methylbenzo[b] quinolizinium bro- 8 mide.--Asolution of 1-(3,4-dimethoxy-2-methyl)benzyl- 2-formylpyridinium bromidesemicarbazone (0.05 g.; M.P. 178-178.5) in 48% hydrobromic acid (1.2ml.) was maintained at for 4 /2 hours. A yellow precipitate formed. Thereaction mixture was poured into tetrahydrofuran (8 ml.) and the yellowprecipitate filtered off (0.03 g.; M.P. 305-308 dec.) and identified asauthentic 8,9- dihydroxy-7-methylbenzo[b]quinolizinium bromide by LR.spectroscopy and thin layer chromatography (2 developing systems).

EXAMPLE 7 Preparation of 8,9-dihydroxy-7-methylbenzo[bJquinoliziniumbromide via 1-(3,4-dimethoxy-2-methyl)benzyl- 2-formylpyridinium bromidephenylhydrazone (a) 1 (3,4 dimethoxy 2 methyl)benzyl 2- formylpyridiniumbromide phenylhydrazone.--A solution of 3,4-dimethoxy-Z-methylbenzylbromide (12.2 g. prepared according to Method A given in Example 1 (b))and Z-pyridinecarboxaldehyde phenylhydrazone (9.8 g.) indimethylformamide (15 ml.) was maintained at room temperature for 18hours. The resulting precipitate was filtered oif and the filtratepoured slowly with stirring into ethyl acetate (800 ml.). The solidwhich was deposited was filtered ofi, recrystallized from isopropanol,and then stirred with water (50 ml.) for 3 hours. The residual solid(3.4 g.) was filtered 01f, dried and used without further purification.

(b) 8,9-dihydroxy 7 methylbenzo[b]quinolizinium bromide.A solution of 1(3,4-dimethoxy 2 methyl) benzyl 2 formylpyridinium bromidephenylhydrazone (0.61 g.) in 48% hydrobromic acid (2.5 ml.) wasmaintained at 100-110" for four hours. The resulting precipitate wasfiltered off (0.30 g.) and recrystallized from dilute hydrobromic acidto give 8,9 dihydroxy 7 methylbenzo[b]quino1izinium bromide (0.20 g.)M.P. 304307 dec. identified by comparison with authentic material by LR.spectroscopy and thin layer chromatography.

EXAMPLE 8 8,9-diacetoxy-methylbenzo b] quinolizinium bromide8,9-diacetoxy-7-methylbenzo [b] quinolizinium bromide (5.0 g.), preparedaccording to the method of Example 3, and sodium hydroxide (2.0 g.) weredissolved in water (19.3 ml.) and 16 g. of crushed ice was added,followed by acetic anhydride (4.25 g.). The solution was made stronglyacid with 48% hydrobromic acid and the resulting crystalline precipitatewas filtered ofi. Two recrystallizations from methanol gave the purediacetate (1.70 g.) as yellow crystals, M.P. 265270.

Analysis.-Calcd for C H BrNO' (percent): C, 55.40; H, 4.14; N, 3.59; Br,2048. Found (percent): C, 55.40; H, 3.96; N, 3.77; Br, 20.27.

EXAMPLE 9 8,9-dimethoxy-4,7-dimethylbenzo [b] quinolizinium bromide (a)1 (3,4 dimethoxy 2 methyl)benzyl 6- methyl 2 formylpyridinium bromideoxime.-3,4 dimethoxy 2 methyl benzyl bromide (12.5 g.) and 6- methyl 2pyridinealdoxime (7.0 g.) were dissolved in dimethylformamide (40 ml.)and the solution was maintained at 30 for 18 hours. The reaction mixturewas poured slowly into ethyl acetate (500 ml.) with stirring. Theresulting precipitate was filtered off (5.20 g.) and used withoutpurification for the next step of the synthesis.

(b) 8,9 dimethoxy 4,7 dimethylbenzo[b]quinolizinium bromide.-1 (3,4dimethoxy 2 methyl)benzyl 6 methyl 2 formyl pyridinium bromide oxime(4.70 g.) was dissolved in 48% hydrobromic acid (11.8 ml.) previouslyheated to and the solution was maintained at that temperature forminutes. The solution was then poured into tetrahydrofuran (250 ml.)with stirring and the stirring maintained for a further 18 hours.Filtation gave 1.4 g. of the potluct. Two recrystallizations fromethanol yielded orange crystals, M.P. 212-2125".

EXAMPLE 1 l-amino-8,9-dimethoxybenzo [b] quinolizinium bromide (a) 3,4dimethoxybenzyl bromide-3,4 dimethoxybenzyl alcohol (53.2 g.) wasdissolved in dry benzene (485 ml.) and the solution was cooled to 10.The solution was saturated with hydrogen bromide while stirring wasmaintained. The reaction mixture was neutralized with anhydrouspotassium carbonate and the s lvent removed on the rotary evaporator togive 67.2 g. of the crude bromide, used without purification for thenext step of the synthesis.

(b) 1 (3,4 dimethoxy)benzyl 2 formylpyridinium bromide oxime.-3,4dimethoxybenzyl bromide (67 g.) and 2-pyridinealdoxime (35.5 g.) weredissolved in dimethylformamide (153 ml.) and the solution was maintainedat for 18 hours. The crystalline product was filtered oil and thefiltrate was poured slowly into ethyl acetate (3000 ml.) with stirring.The resulting amorphous precipitate was filtered oil and combined withthe crystalline material to give a yield of 87.5 g. of the crude saltused without purification for the next step of the synthesis. Therecrystallizations from methanol gave the pure salt, M.P. 168-l71.5 aspale yellow crystals.

Analysis.--Calcd for C H BrN O (percent): C, 50.99; H, 4.95; N, 7.93;Br, 22.63. Found (percent): C, 51.29; H, 4.96; N, 7.86; Br, 22.51.

(c) 11 amino 8,9 dimethoxybenzo[b]quinolizinium bromide. 1 (3,4dimethoxy)benzyl 2 formylpyridinium bromide oxime (74.3 g.) wasdissolved in 48% hydrobromic acid (186 ml.) heated on the steam bath.The resulting solution was poured into tetrahydrofuran (3700 ml.) andthe stirring was maintained for a further 18 hours. Filtration gave 62.4g. of the crude product which was extracted with 2 x 3 liter portions ofboiling ethanol. The resulting ethanol solutions deposited a total of8.4 g. of crystalline materianl on cooling and this was combined withthe residue from the ethanol extractions (1.4 g.). The combined materialwas recrystallized twice from ethanol to give 3.92 g. of the pure aminocompound as yellow crystals, M.P. 267-2675".

AnaIysis.-Calcd for C H BrN O (percent): C, 53.75; H, 4.51; N, 8.36; Br,23.84. Found (percent): C, 53.85; H, 4.45; N, 8.66; Br, 23.67.

EXAMPLE 11 8,9,1 l-trihydroxybenzo [b] quinolizinium bromide 11 amino8,9 dimethoxybenzo[b]quinolizinium bromide (2.92 g.) was dissolved in48% hydrobromic acid (12 ml.) and the solution was refluxed for 3 hours.The reaction mixture was cooled to room temperature, and the productfiltered oil and recrystallized twice from dilute hydrobromic acid togive 1.2 g. of yellow crystals, M.P. 350.

Analysis-Calcd for C H B1NO (percent): 0. 50.67; H, 3.27; N, 4.55. Found(percent): C, 50.56; H, 3.70; N, 4.64.

EXAMPLE 12 8,9-dihydroxybenzo [b] quinolizinium chloride A mixture of3,4-dimethoxybenzyl bromide (20.1 g.), pyridine-Z-carboxaldehyde (10.05g.) and dimethylformamide (2.5 ml.) was maintained at room temperaturefor 24 hours. The resulting glassy mass was washed with ether.Concentrated hydrochloric acid (100 ml.) was then added, and the mixturewas kept at 100 for two hours. The reaction mixture was cooled to roomtemperature, and the 10 resulting crystalline precipitate was filteredoff. This material was taken up in water and passed through a column ofAmberlite IRA 400 (chloride form). The solution was evaporated todryness to give 3.91 g. of crude 8,9-dimethoxybenzo [b] quinoliziniumchloride.

A mixture of 8,9 dimethoxybenzo[b]quinolizinium chloride (3.7 g.) andconcentrated hydrochloric acid (50 ml.) was refluxed for 18 hours. Thereaction mixture was cooled to room temperature and the resultingcrystalline precipitate was filtered off, recrystallized twice fromdilute hydrochloric acid and once from. methanol to give 520 mg. ofyellow crystals, M.P. 350.

EXAMPLE 13 1 l-amino-9, l 0-dimethoxy-7-methylbenzo [b quinoliziniumbromide (a) 4,5 dimethoxy-2-methylbenzyl bromide (Method A).A mixture of3,4-dimethoxytoluene (10 g.), glacial acetic acid (11 g.) andmonobromimethylmethyl ether (17 g.) was maintained at 30 for 5 hours.The reaction mixture was poured into ice-Water, the mixture extractedwith ether, and the ether dried over anhydrous magnesium sulfate andevaporated under reduced pressure to give 15 g. of the desired productas a straw colored oil, used without purification for the next step ofthe synthesis.

(Method B).-A mixture of 3,4-dimethoxyt0luene (182 g.), paraformaldehyde(40 g), benzene (600 ml.) and 48% hydrobromic acid (137 ml.) was cooledto 0 and saturated with hydrogen bromide with ice cooling. The phaseswere separated and the organic layer was washed with saturated brine anddried over anhydrous magnesium sulfate. On evaporation of the solvent,the product was obtained as a semicrystalline mass (175 g).Recrystallization from hexane gave material of M.P. 31.5-33".

(b) 1-(4,5-dimethoxy Z-methyl)benzyl-2-formylpyridinium bromideoxime.-4,5 dimethoxy-Z-methylbenzyl bromide (12.5 g.) and2-pyridinealdoxime (6.3 g.) were dissolved in dimethylformamide (32 ml.)and the solution was maintained at 30 for 18 hours. The crystallineproduct was filtered off and the filtrate poured slowly into ethylacetate (500 ml.) with stirring. The resulting amorphous solid wasfiltered oil? and combined with the crystalline material to give a totalyield of 14.3 g. of the quaternary salt, used without purification forthe next step of the synthesis. Two recrystallizations from methanolgave the pure material as colorless crystals, M.P. 178.5-181".

Analysis-Caled for C1 H BINgO (percent): C, 52.32; H, 5.22; N, 7.63; Br,21.76. Found (percent): C, 52.14; H, 5.24; N, 7.43; Br, 22.01.

(c) 11 amino 9,10-dimethoxy 7 methylbenzo[b] quinoliziniumbromide.--1-(4,5 dimethoxy 2 methyl) benzyl-Z-formylpyridinium bromideoxime (114 g.) was dissolved in 48% hydrobromic acid (270 ml.) andheated on the steam bath. The resulting solution was poured intotetrahydrofuran (8000 ml. in two batches) and the stirring wasmaintained for a further 18 hours. Filtration gave 84 g. of the crudeproduct which was extracted with 3 x 4 liter portions of boilingethanol. The resulting ethanol solutions were reduced in volume to 9liters and deposited 24 g. of crystalline material on cooling. Threerecrystallizations from ethanol gave 400 mg. of the amino compound, M.P.264-265", as orange crystals.

EXAMPLE 14 9, 10-dihydroxy-7-methylbenzo [b] quinolizinium bromide (a)9,10-dimethoxy 7 methylbenzo [b]quinolizinium bromide.-1(4,5-dimethoxy-2-methyl(benzy1-2-formylpyridinium bromide oxime (11.4g.) was dissolved in 48% hydrobromic acid (29 ml.) previously heated toand the solution was maintained at that temperature for 5 minutes. Thesolution was poured into tetrahydrofuran (454 ml.) with stirring and thestirring was maintained for a further 18 hours. The resulting product(5.2

1 1 g.) was filtered off and used without purification for the next stepof the synthesis.

(b) 9,10-dihydroxy 7 methylbenzo[b]quinolizinium bromide-A mixture of9,l-dimethoxy-7-methylbenzo- [b]quinolizinium bromide (5.0 g.) and 48%hydrobromic acid (21 ml.) was refluxed for 3 hours, and the reactionmixture cooled to room temperature. The crystalline product was filteredoff and recrystallized from dilute hydrobromic acid to give 3.50 g; ofthe pure material. M.P. 350", as orange needles.

Analysis.Calcd for C H BrNO (percent): (3. 54.92; H, 3.95; N, 4.58; Br,26.11. Found (percent): C, 55.00; H, 3.90; N, 4.60; Br, 25.98.

EXAMPLE 9, 10-dihydroxy-7-methylbenzo [b] quinolizinium chloride (a)9,10-dimethoxy 7 methylbenzo [b]quinolizinium chloride.A mixture of4,5-dimethoxy-2-methylbenzyl bromide (26.5 g.),pyridine-2-carboxaldehyde (12.5 g-) and dimethylformamide (1.5 ml.) wasmaintained at room temperature for 24 hours. The resulting glassy masswas triturated with ether and filtered off under nitrogen as an orangepowder. This material was dissolved in concentrated hydrochloric acid(100 ml.) and the solution maintained at 100 for two hours. The reactionmixture was diluted to 1000 ml. and passed through a column of Dowex 21K (chloride form). Evaporation of the eluant gave the product as a redglass (32.9 g.).

(b) 9,10-dihydroxy 7 methylbenzo[b]quinolizinium chloride.9,10-dimethoxy7 methyl-benzo[b]quinolizinium chloride (32.5 g.) was dissolved inconcentrated hydrochloric acid (230 ml.) and the solution was refluxedfor 18 hours. The reaction mixture was cooled to room temperature andthe resulting crystalline precipitate was filtered off andrecrystallized once from dilute hydrochloric acid to give the pureproduct (7.2 g.) as orange needles, M.P. 342 dec.

Analysis.Calcd for C H CINO (percent): C, 64.25; H, 4.62; N, 5.36; Cl,13.55. Found (percent): C, 64.19; H, 4.69; N, 5.37; C], 13.50.

EXAMPLE 16 9,10-diacetoxy-7-methylbenzo [b1quinolizinium bromide Amixture of 9,10 dihydroxy 7 methylbenzo[b] quinolizinium bromide (5.0g.), prepared according to the method of Example 14, acetic anhydrideml.), and concentrated sulfuric acid (0.5 g.) was refluxed until all thesolid had dissolved. The reaction mixture Was cooled, the crystallineproduct filtered off and recrystallized four times from ethanol to yield520 mg. of the pure diacetate as yellow crystals, M.P. 229-231 dec.

Analysis.-Calcd for C H BrNO (percent): C, 55.39; H, 4.14; N, 3.59; Br,20.48. Found (percent): C, 55.16; H, 4.28; N, 3.70; Br, 20.25.

EXAMPLE 17 9,10-dipropionoxy-7-methylbenzo [b]quinolizinium bromide Amixture of 9,10 dihydroxy 7 methylbenzo[b] quinolizinium bromide (5.0g.), prepared according to the method of Example 14 propionic anhydride(51 ml.) and concentrated sulfuric acid (0.5 g.) was refluxed until allthe solid had dissolved. The reaction mixture was cooled, thecrystalline product filtered OE and recrystallized twice from ethanol togive 1.3 g. of the pure d propionate as yellow crystals, M.P. 22-5-226.

AnaZysis.Calcd for C H BrNQ, (percent): C, 57.43; H, 4.82; N, 3.35; Br,19.11. Found (percent): C, 57.56; H, 4.85; N, 3.42; Br, 19.06.

EXAMPLE 1s 9,10-dihydroxy-7-isopropylbenzo [b]quinolizinium bromide (a)3,4-dimethoxycumene.4 isopropyl catechol (230 g.) was dissolved in asolution of sodium hydroxide (168 g.) in water (1210 ml.). The solutionwas cooled to 15 and dimethyl sulfate (325 ml.) was added to the stirredand cooled reaction mixture during 1 /2 hours. The mixture was warmed onthe steam bath for one hour and refluxed for 18 hours. After cooling,the organic phase was separated and the aqueous phase extracted withbenzene (2 x 250 ml.). The combined organic solutions were washed with10% aqueous sodium hydroxide until no phenolic material remained (ferricchloride test) and then with water. The benzene was removed bydistillation through a Vigreux column at atmospheric pressure, and theresidue distilled under reduced pressure to yield a pale yellow liquid(223 g.(, B.P. 123130/23 mm.

(b) 4,5 dimethoxy 2 isopropylbenzyl bromide (Method A).-A mixture of 3,4dimethoxycumene (41 g.), glacial acetic acid (38 g.), andmonobromomethylmethyl ether (60 g.) was maintained at 30 for 5 hours.The reaction mixture was poured into ice-water, the resulting oil wasextracted from the water with ether, the ether dried over anhydrousmagnesium sulfate, and evaporated under reduced pressure to give theproduct as a pale yellow oil (54.7 g.), used without furtherpurification for the next step of the synthesis.

(Method B).-A mixture of 3,4 dimethoxy cumene (60 g.), paraformaldehyde(11 g.), 48% hydrobromic acid (38 ml.), and benzene (166 ml.) was cooledto 0 with stirring and was saturated with hydrogen bromide with icecooling. The organic phase was separated, dried over anhydrous magnesiumsulfate, and the solvent removed under reduced pressure to give thecrude benzylbromide (86 g.) used without purification for the next stepof the synthesis.

(c) 1 (4,5 dimethoxy 2 isopropyl)benzyl 2- formylpyridinium bromideoxime.-4,5 dimethoxy 2- isopropylbenzyl bromide (54.7 g.) andZ-pyridinealdoxime (20.9 g.) were dissolved in dimethylformarnide 132ml.) and the solution maintained at 30 for 18 hours. The reactionmixture was added slowly to ethyl acetate (3000 ml.) and the resultingamorphous product (64.2 g.) was filtered off and used withoutpurification for the next step of the synthesis. One recrystallizationfrom methanol/ethyl acetate gave the pure quaternary salt, M.P. 147-148dec.

Analysis.-Calcd for C H B1N O (percent): C, 54.68; H, 5.86; N, 7.03; Br,20.22. Found (percent): C, 54.06, 54.45, 54.35; H, 5.60, 5.67, 5.70; N,6.91; Br, 20.72, 20.49.

(d) 9,10 dimethoxy 7 isopropylbenzo[b]quinoli zinium bromide.1 (4,5dimethoxy 2 isopropyl) benzyl 2 forrnylpyridinium bromide oxime (43.1g.) was dissolved in 48% hydrobromic acid ml.) previously heated to Thesolution was maintained at that temperature for 5 minutes, and thenadded slowly to tetrahydrofuran (4000 ml.) with stirring. The stirringwas continued for a further 18 hours and the resulting crystallineproduct (17.4 g.) filtered oh and used Without purification for the nextstep of the synthesis.

(e) 9,10 dihydroxy 7 isopropylbenzo[b]quinoli zinium bromide.-A solutionof 9,10 dimethoxy 7- is0propylbenzo[b]quinolizinium bromide (10 g.) in48% crystalline product was filtered from the hot reaction mixture andrecrystallized three times from dilute hydrobromic acid to give 900 mg.of the pure salt as orange needles, M.P. 350.

Analysis.-Calcd for C H BrNO (percent): C, 57.49; H, 4.83; N, 4.19; Br,23.91. Found (percent): C, 57.36; H, 4.65; N, 4.24; Br, 26.6.3.

13 EXAMPLE 19 1 1-amino-8,9, l O-trimethoxybenzo [b] quinoliziniumbromide (a) 3,4,5 trimethoxybenzyl bromide.-3,4,5 trime thoxybenzylalcohol (40.0 g.) was dissolved in dry benzene (312 ml.) and thesolution was cooled to and saturated with hydrogen bromide withstirring. The reaction mixture was neutralized with anhydrous potassiumcarbonate, filtered, and'dried over anhydrous magnesium sulfate.Evaporation of the solvent gave the bromide as an almost colorless oil(43.3 g.) used without purification for the next step of the synthesis.

(b) 1 (3,4,5 trimethoxy)benzyl 2 -formylpyridinium bromideoxide-3,4,5-trimethoxybenzyl bromide (43.0 g.) and Z-pyridinealdoxime(32.3 g.) were dissolved in dimethylformamide (203 ml.) and theresulting solution was maintained at 30 for 18 hours. The crystallineproduct was filtered off and the filtrate poured into ethyl acetate(2000 ml.). The resulting amorphous product was filtered off andcombined with the crystalline material to give a total yield of 51.2 g.of the crude salt used without purification for the next step of thesynthesis. Two recrystallizations from methanol gave the pure salt ascolorless crystals, M.P. 155-157.5.

Analysis.-Calcd for C H BrN O (percent): C, 50.14; H, 5.00; N, 7.32; Br,20.85. Found (percent): C, 49.80; H, 4.80; N, 7.32; Br, 20.73.

(c) 11 amino 8,9,10 trimethoxybenzo[b]quinolizinium bromide.--1 (3,4,5trimethoxy)benzyl 2- formylpyridinium bromide oxime (51.0 g.) wasdissolved in 48% hydrobromic acid (128 ml.) heated on the steam bath.The resulting solution was poured into tetrahydrofuran (2500 ml.) withstirring and the stirring was maintained for 18 hours. The crystallineproduct (34.1 g.) was filtered off and recrystallized three times fromethanol to give 4.2 g. of the pure amino-compound as orange crystals,M.P. 223-223.5.

Analysis.Calcd for C H BrN O (percent): C, 52.61; H, 4.69; N, 7.67; Br,21.88. Found (percent): C, 52.53; H, 4.90; N, 7.62; Br, 21.75.

EXAMPLE 20 8,9,10,11 tetrahydroxybenzo[b-] quinolizinium bromide 11amino 8,9,10 trimethoxybenzo[b]quinolizinium bromide (5.0 g.) preparedaccording to the method of Example 19, was dissolved in 48% hydrobromicacid ml. and the solution refluxed for 3 hours. The reaction mixtureswas cooled to room temperature and the prodnot removed by filtration.Two recrystallizations from dilute hydrobromic acid gave the desiredproduct as a yellow amorphous solid, 1.93 g. M.P. 350.

EXAMPLE 21 8,9,10-trihydroxybenzo [b] quinolizinium bromide (a) 8,9,10trimethoxybenzo[b]quinolizinium bromide.1 (3,4,5 trimethoxy)benzyl 2formylpyridinium bromide oxime (25 g. prepared according to the methodgiven in Example 19 (b)) was dissolved in 48% hydrobromic acid (63 ml.)previously heated to 110. The resulting solution was maintained at 110for S-minutes and then poured slowly with stirring into tetrahydrofuran(2500 ml.). Stirring was maintained for 18 hours and the precipitate wasfiltered off to give 12.7 g. of the crude salt, used without furtherpurification for the next step of the synthesis.

(b) 8,9,10 trihydroxybenzo[b]quinolizinium bromide.-A mixture of 8,9,10-trimethoxybenzo[b]quinolizinium bromide (10 g.) and 48% hydrobromic acid(42 ml.) was refluxed for 3 hours. The reaction mixture was cooled andthe crystalline material filtered off and recrystallized from dilutehydrobromic acid to give 7.2 g. of the product as yellow crystals, M.P.350.

14 Analysis.-Calcd for C H BrNO (percent): C, 50.67; H, 3.27; N, 4.55;Br, 25.94. Found (percent): C, 50.67; H, 3.24; N, 4.59; Br, 26.07.

EXAMPLE 22 1 1-amino-7,S-dimethoxybenzo [b] quinolizinium bromide (a)2,3 dimethoxybenzyl bromide-23 dimethoxybenzyl alcohol (75.0 g.) wasdissolved in benzene (683 ml.) and the solution cooled to 10. Thesolution was saturated with hydrogen bromide, neutralized with anhydrouspotassium carbonate, filtered, and dried over anhydrous magnesiumsulfate. Evaporation of the solvent gave the bromide as a colorless oil(90.3 g.) used without purification for the next step of the synthesis.

(b) 1 (2,3 dimethoxy)benzyl 2 formylpyridinium bromide oxime.-2.3dimethox'ybenzyl bromide (90.3 g.) and 2-pyridinealdoxime (47.9 g.) weredissolved in dimethylformamide (63 ml.) and the resulting solutionmaintained at 30 for 18 hours. The crystalline product was filtered oifand the filtrate poured into ethyl acetate (4000 ml.). The resultingamorphous precipitate was filtered off and combined with the crystallinematerial to give a total yield of 118.2 of the crude salt, used withoutpurification for the next step of the synthesis.

(c) 11 amino 7,8 dimethoxybenzo[b]quinolizinium bromide.-l (2,3dimethoxy)benzyl 2 formylpyridinium bromide oxime (30.7 g.) wasdissolved in 48% hydrobromic acid heated on the steam bath. Theresulting solution was poured into tetrahydrofuran (1500 ml.) withstirring and the stirring maintained for 18 hours. Filtration yielded19.3 g. of the crude product. Three recrystallizations from ethanol gavethe pure material (1.2 g.) as orange crystals, M.P. 246-255.

Analysis.-Calcd for C H BrN 0 (percent): C, 53.75; H, 4.51; N, 8.36; Br,23.84. Found (percent): C, 54.02; H, 4.60; N, 8.64; Br, 23.70.

EXAMPLE 23 8 ,9-diethoxy-7-methylbenzo [b] quinolizinium bromide (a) 2,3dieth0xytoluene.--3 methylcatechol (250 g.) was dissolved in a solutionof sodium hydroxide (224. g.) in water (1600 ml.) and the resultingsolution was cooled with ice/ salt. Diethyl sulfate (600 ml.) was slowlyadded with stirring, the temperature being maintained between 0 and -7.The reaction mixture Was heated on the steam bath for 3 hours, thenrefluxed for 18 hours and allowed to cool to room temperature. Theorganic layer was separated and the Water layer was extracted thoroughlywith benzene. The combined organic solutions were washed with 10% sodiumhydroxide solution until no phenolic material remained (FeCl test) andthen with water. The benzene was distilled oif at atmospheric pressurethrough a Vigreux column and the residue was distilled to give 219.4 g.of the product, B.P. 123-l27/ 12 mm.

(b) 3,4-diethoxy-Z-methylbenzyl bromide-A mixture of 2,3-diethoxytoluene(213 g.) benzene (590 ml.), paraformaldehyde (39.4 g.) and 48%hydrobromic acid ml.) was cooled to 0 with stirring and saturated withhydrogen bromide. The organic phase was washed with saturated brine (3 xml.) dried over anhydrous magnesium sulfate and the solvent was removedunder reduced pressure. The resulting oil was poured into icewater (1000ml.) and the crystalline product was filtered off and recrystallizedfrom petroleum ether (B.P. 30- 60; charcoal) to give 154 g. of thebenzyl bromide, M.P. 39-44.

(c) l-(3,4-diethoxy-2-methyl)benzyl 2 formylpyridinium bromide oXime.-Asolution of 12.2 g. of 2- pyridinealdoxime and 27.3 g. of3,4-diethoxy-2-methylbenzylbromide in 30 ml. of dimethylformamide wasmaintained at room temperature for four days. The resulting precipitatewas filtered Off and the filtrate poured slowly'with stirring into 1000ml. of ethyl acetate. The

solid which was deposited was filtered 011 and combined with thematerial obtained directly from the reaction mixture. Recrystallizationfrom 2B ethanol gave 8.5 g. of the pure product together with 10.3 g. ofless pure material.

Analysis.-Calcd for C H BrN O (percent): C, 54.68; H, 5.86; N, 7.08; Br,20.22. Found (percent): C, 54.57; H, 5.84; N, 7.14; Br, 20.46.

((1) 8,9 diethoxy 7 methylbenzo[b]quinoliziniumbromide.-1-(3,4-diethoxy-2-methyl)benzyl 2 formylpyridinium bromideoxime (5.5 g.) was dissolved in 48% hydrobromic acid (15 ml.) previouslyheated at 110, and the solution was maintained at that temperature for 6minutes. The solution was poured into tetrahydrofuran (200 ml.) withstirring. The resulting yellow precipitate was filtered off andrecrystallized from methanol/isopropanol to give thebenzo[b]quinolizinium salt (0.6 g.) as yellow crystals, M.P. 2l3220 dec.

EXAMPLE 24 8,9-dimethoxy-3-ethyl-7-methylbenzo [b] quinolizinium bromide(a) 5 ethyl 2 pyridinealdoxime.-A mixture of 5- ethyl-2-methylpyridine(24 g.), glacial acetic acid (80 ml.) and hydrogen peroxide (18 ml.) wasmaintained at 80 for three hours. An additional portion of 30% hydrogenperoxide (6 ml.) was added and the mixture was maintained at 80 for afurther 3-hour period. The volatile solvents were removed under reducedpressure (water pump) and the residue dissolved in acetic anhydrideml.). The mixture was heated to 95, which initiated and exothermicreaction. The reaction mixture refluxed and refluxing was maintained fora further 2 hours. The solution was distilled under reduced pressure(water pump) and after a forerun, 2 acetoxymethyl-S- ethyl-pyridine(15.0 g., B.P. l38-40/ 12 mm.) was obtained.

A mixture of the 2-acetoxymethyl-S-ethylpyridine obtained above, glacialacetic acid (70 ml.), and 30% hydrogen peroxide (16 ml.) was maintainedat 80 for 3 hours. An additional portion of 30% hydrogen peroxide (8ml.) was added and the mixture was maintained at 80 for a further 3-hourperiod. The volatile solvents were removed under reduced pressure (waterpump) and the residue was dissolved in 6N HCl (60 ml.). The solution Washeated on the steam bath for one hour and the bulk of the hydrochloricacid was removed on the rotary evaporator. The residue was dissolved inwater, made basic by the addition of aqueous sodium hydroxide, andextracted thoroughly with ether. The ether was removed on the rotaryevaporator and the residue distilled to give 5-ethyl-2-formylpyridine(3.76 g.; B.P. 85-106/12 mm.).

A solution of hydroxylamine was prepared from hydroxylaminehydrochloride (1.94 g.), water (10 ml.), and sodium bicarbonate (2.35g.). A solution of the aldehyde obtained above in ethanol (10 ml.) wasadded and the mixture heated on the steam bath for one hour. Thereaction mixture was cooled to room temperature, and5-ethyl-2-pyridinealdoxime (2.99 g.: M.P. 1489) was obtained.

(b) 1-(3,4-dimethoxy 2 methyl)benzyl 5 ethyl- 2-forrnylpyridiniumbromide oxime. A solution of 3,4- dimethoxy-Z-methylbenzyl bromide (3.83g.: prepared according to Method A given in Example 1 (b)) and 5-ethyI-Z-pyridinealdoxime (2.34 g.) in dimethylformamide (10 ml.) wasmaintained at room temperature for 18 hours and poured slowly withstirring into ethyl acetate (200 ml.). The resulting solid (5.6 g.) wasfiltered 01f. A portion of this material 3.0 g.) was recrystallized fromisopropanol to give the pure quaternary salt (1.2 g.: M.P. 142-143") ascolorless crystals.

Analysis.-Calcd for C H BrN O (percent): C, 54.68; H, 5.87; N, 7.09; Br,20.21. Found (percent): C, 54.74; H, 5.93; N, 7.06; Br, 20.26.

(c) 8,9 dimethoxy 3 ethyl 7 methylbenzo[b]- quinolizinium bromide-1 (3,4dimethoxy-2-methyl)- benzyl-5-ethyl-2-formylpyridinium bromide oxime(2.1 g.) was dissolved in 48% hydrobromic acid (4.5 m1.) previouslyheated to 110, and the solution was maintained at that temperature forfive minutes. The solution was poured into tetrahydrofuran (70 ml.) withstirring. The resulting precipitate was filtered 011 and recrystallizedfrom isopropanol to give the benzo[b]quinolizinium salt (0.8 g.) asyellow crystals, M.P. 162.5167.5.

EXAMPLE 25 8,9-dimethoxy-1,7-dimethylbenzo [b] quinolizinium bromide (a)1-(3,4-dimethoxy 2 methyl)benzyl 2 formyl- 3-methylpyridinium bromideoxime.-A solution of 3- methyl 2 pyridinealdoxime (6.8 g.: prepared bythe method of S. Ginsburg and I. B. Wilston, J. Amer. Chem. Soc., 79,481 (1957)) and 3,4-dimethoxy-Z-methylbenzyl bromide (12.2 g.; preparedaccording to either method given in Example l(b)) in dimethylformamide(35 ml.) was maintained at room temperature for two hours. Theprecipitate was filtered off and recrystallized from ethanol to give thepure quaternary salt (7.0 g.) as colorless crystals, M.P. 154-155.5.

Analysis.-Calcd for C17H21BI'N2O3 (percent): C, 53.55; H, 5.56; N, 7.35;Br, 20.96. Found (percent): C, 53.54; H, 5.55; N, 7.31; Br, 21.24.

(b) 8,9 dimethoxy 1,7 dimethylbenzo[b]quinoliziniumbromide.1-(3,4-dimethoxy 2 methyl)benzyl- 2-formyl-3-methylpyridiniumbromide oxime (5.0 g.) was dissolved in 48% hydrobromic acid (13 ml.)previously heated to 110, and the solution was maintained at thattemperature for six minutes. The solution was poured intotetrahydrofuran ml.) with stirring. The resulting precipitate wasfiltered off and recrystallized from methanol/isopropanol to give thebenzo[b]quinolizinium salt (2.0 g.) as yellow crystals, M.P. 2029.

As noted above, the compounds of this invention have usefulpharmacological effects. To illustrate the cardiovascular activity ofthese compounds, the following hypotensive effects were observed inChloralose/urethane anaesthetized cats when the indicated compounds wereadministered intravenously:

As indicated in the foregoing table, administration of the compounds ofthis invention causes a significant lowering of blood pressure(drug-induced value).

The antipyretic etfects of these compounds were measured byadministering certain of them interperitoneally to rats in doses of 50milligrams per kilogram of body weight. Rectal temperature (in degreesF.) was measured at the time of administration and at 1, 2 and 3 hoursafter administration. The difference between the temperature at the 1-,2-, and 15-hour intervals and the temperature at the time ofadministration were added to obtain the sum of the differences. The dataare reported in Table II:

TABLE II Compound: 7 Sum of difference 8,9-dimethoxy 7methylbenzo[b]quinolizinium bromide 15.2 8,9-dihydroxy 7methylbenzo[b]quinolizinium bromide 5 .7 11 amino 8,9 dimethoxybenzo[b]quinolizinium bromide 4.6 ll-amino 8,9,10 trimethoxybenzo[b]quinolizinium bromide 11.3 Antipyrine 2.7

As indicated in the foregoing table, the compounds of this inventionsignificantly exceeded the well known antipyretic agent antipyrine inantipyretic effect.

As an illustration of the central nervous system activity of thesecompounds, 9,10 dihydroxy-7-methylbenzo- [b]quinolizinium bromide whenadministered to gerbils at a dose range of 5 to 20 milligrams perkilogram of body weight interperitoneally in the Sidman AvoidanceProcedure, elicited responses indicative of tranquilizing activityanalogous to that produced by known tranquilizing agents such aschlorpromazine.

We claim:

1. A method for treating a mammal suffering from hypertension whichmethod comprises administering to said mammal a therapeuticallyeffective amount of a compound of the formula Rr-o 1 in which R, islower alkyl,

R is hydroxy or lower alkanoxy,

R is hydrogen or lower alkyl, and

X is chlorine or bromine.

2. A method according to claim 1 in which the compound is8,9-dimethoXy-7-methylbenzo[b]quinolizinium bromide.

3. A method according to claim 1 in which the compound 8,9-dihydroxy 7methylbenzo[b]quinolizinium bromide.

References Cited UNITED STATES PATENTS 3,375,253 3/1968 Fields et al260-286 3,408,352 10/1968 Hardtman 260-288 3,426,027 2/1969 Muller260-289 3,489,756 1/ 1970 Fields et a1. 260289 X STANLEY J. FRIEDMAN,Assistant Examiner

